Mendeleev Communications Electronic Version, Issue 1, 1999 (pp. 1–44) New version of mononuclear heterocyclic rearrangement Nina N. Makhova* and Alexander N. Blinnikov N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 117913 Moscow, Russian Federation. Fax: +7 095 135 5328; e-mail: mnn@cacr.ioc.ac.ru Thermal recyclization of the 3-diazenofuroxanyl unit to form the 4-nitro-1,2,3-triazole fragment has been found in noncondensed 1,2,5-oxadiazol 2-oxide derivatives (3,3'-azofuroxans) with acetamido substituents in the 4,4'-positions.Recently,1 we have developed a general preparative methods for the synthesis of azo- and azoxyfuroxans. This work is devoted to the study of their reactivity. It has been found unexpectedly that 4,4'-bis(acetamido)-3,3'-azofuroxan 1b upon heating gives a new compound with the same molecular formula. According to the 1H and 13C NMR spectroscopic data, this compound contains two different acetamido groups.The 13C NMR spectrum contains four downfield signals (117.68, 144.73, 148.02 and 150.14 ppm), two of which (117.68 and one of the downfield signals at 148.02 or 150.14 ppm) are most likely assigned to the furoxan ring.2 Two other signals can be assigned to another aromatic heterocycle. In addition, a signal of the nitro group (–26.0 ppm) appeared in the 14N NMR spectrum.Therefore, a molecule of the new compound contains two aromatic heterocycles (one of which is the furoxan ring), two different acetamido groups and one nitro group. To obtain a simpler spectral pattern, the acetamido groups in the new compound were oxidized to nitro groups by a mixture of conc. H2O2 and conc.H2SO4. This reaction afforded a mixture of two new compounds in the 8:1 ratio, which were separated by chromatography on SiO2. According to the 14N NMR data, the prevailing compound contained three nitro groups, two of which had equal chemical shifts (–37.0 ppm), and the third nitro group had a chemical shift of –39.0 ppm.The 13C NMR spectrum exhibited only three signals at 124.48, 145.41 and 147.98 ppm, two of which were broadened and appeared as triplets due to spin–spin coupling with atoms of the 14N nitro groups. This shape of the signals is typical of C–NO2 fragments. The presence of the C–NO2 fragments was confirmed by narrowing of these signals in the 13C NMR spectrum after decoupling of 14N in both of the nitro groups.The ratio of the integral intensities showed that the carbon atom with a chemical shift of 124.48 ppm is bound to a nitro group, and two other nitro groups are linked to the carbon atoms with chemical shifts of 147.98 ppm. Obviously, the compound obtained contained two equivalent C–NO2 fragments, which are a part of a heteroaromatic ring. Two other signals in the 13C NMR spectrum belong to the furoxan ring.The comparison of the elemental analysis and NMR data suggests that the structure of this compound is 4-nitro-3-(4,5- dinitro-1,2,3-triazol-2-yl)furoxan 2b. The 15N NMR spectrum confirmed the presence of the triazole ring (two equivalent signals with the chemical shifts of 36.31 ppm and a signal with the chemical shift of 162.75 ppm; these data agree with the data published for 15N spectra of 2-substituted 1,2,3-triazoles3).The second compound is its isomer 2c. (It is known that the furoxan ring is prone to tautomerism,4 especially when two electronwithdrawing substituents are present). Thus, the primary product obtained by heating of azofuroxan 1b is the product of its thermal rearrangement, viz., 4-acetamido-3-(5-acetamido-4-nitro- 1,2,3-triazol-2-yl)furoxan 2a.Starting diazenofuroxan 1b was synthesised by the acetylation of 4,4'-diamino-3,3'-azofuroxan 1a with acetic anhydride in the presence of a catalytic amount of conc. H2SO4 (Scheme 1). Two rearrangements resulting in the 1,2,3-triazole ring are known in the furoxan series.The first rearrangement is the formation of 1,2,3-triazol 1-oxide derivatives under the action of amide anions on benzofuroxans5 or of primary aliphatic amines on 4-amino-3-nitrofuroxans.6 This transformation is probably initiated by the nucleophilic attack of an amide anion or amine on the N(5) atom of the furoxan ring. The second rearrangement (a version of the Boulton–Katritzky rearrangement7) is the recyclization of 4-aryldiazeno-5-nitrobenzofuroxan 4 to 2-aryl-4,7-dinitrobenzo-1,2,3-triazole 5.Starting benzofuroxan 4 was not isolated but appeared as an intermediate product upon heating of 2,6-dinitro-3-azidoaryldiazenobenzene 3. In this case, the reaction also starts from the nucleophilic N O N NH2 N N N O N NH2 O O N O N NHAc N N N O N NHAc O O i N N N O2N AcHN N O N AcHN O ii iii N N N O2N O2N N O N O2N O 1a 1b 2a 2b (4-NO2-furoxan) 2c (3-NO2-furoxan) 2b:2c = 8:1 Scheme 1 Reagents and conditions: i, Ac2O (20 mol), H2SO4 (cat.amount), 30 °C, 10 min; ii, AcOH:Ac2O = 4:1, 50 °C, 3 h; iii, conc. H2O2/conc. H2SO4, 22–24 °C, 40 min. O2N NO2 N3 N N Ar 3 155–160 ºC diglyme, 20 min O2N N N Ar N O N O O2N N N Ar N O N 4 NO2 N N N NO2 O 5 O Scheme 2 Ar N A B D X Y RZ N X Y Z A B DR Scheme 3Mendeleev Communications Electronic Version, Issue 1, 1999 (pp. 1–44) attack of a diazene unit on the N(5) atom of the furoxan ring (Scheme 2). The rearrangement found is formally similar to the latter case, but it occurs with the noncondensed furoxan system. Moreover, several mononuclear heterocyclic rearrangements are known,8 which correspond to the general Scheme 3.However, the rearrangement under consideration can be presented by none of these schemes, because, first, azofuroxans, in particular, 1a and its dinitro analogue 1h, are planar systems with the trans arrangement of furoxan rings with respect to the azo group9 and hence it is difficult to imagine the nucleophilic attack of the diazene unit on the N(5) atom in compound 1b.Second, the isomerisation of the furoxan ring as the first stage of the reaction should be ruled out, because the acetamido and nitro groups in compound 2a are bound to two different carbon atoms of the triazole ring. To obtain additional information on this reaction, we used other 3,3'-azofuroxans with various substituents in the 4,4'- positions, namely, 4,4'-diamino-, 4,4'-bis(dimethylamino)-, 4,4'- bis(N-methylacetamido)- and 4,4'-diphenyl-azofuroxans 1a,c–e, respectively.We found that amino derivatives 1a,c remained unchanged upon heating at 100 °C for 2 h. Heating of diphenyl derivative 1e at 110 °C for 10 h resulted in the formation of a mixture of the starting compound 1e and products of isomerisation of one and two furoxan rings 1f and 1g, respectively (Scheme 4).Only bis(acetamido) derivative 1d undergoes the aforementioned rearrangement to form a mixture of isomeric triazolylfuroxans 2d and 2e in the 1:2 ratio. The starting azofuroxan 1c was synthesised by nucleophilic substitution for the nitro groups in 3,3'-azo-4,4'-dinitrofuroxan 1h, and 1d was obtained by the acetylation of 1c (Scheme 5).† Thus, it was established that the presence of 4,4'-acetamido groups in the starting 3,3'-azofuroxan 1 is the key condition for this rearrangement.Based on this fact, we can suggest a hypothetical scheme of this reaction, which includes two successive rearrangements. The first rearrangement is the transformation of one of the acetamidofuroxan fragments in compound 1 into the 1,2,4-oxadiazole unit with the cleavage of the O(1)–N(5) bond of the furoxan ring and the release of a nitromethylene fragment (intermediate 6).The second rearrangement is the transformation of compound 6 into 2. † All new compounds exhibited satisfactory elemental analysis data and their structures were confirmed by IR, NMR and mass spectroscopy. Spectroscopic data: 1H NMR (300MHz), 13C NMR (75.47 MHz), standard TMS; 14N and 15N NMR (21.6 MHz), internal standard MeNO2. 3,3'-Azo-4,4'-bis(acetamido)furoxan 1b: yield 93%, mp 196–198 °C, Rf 0.49 (CHCl3:PriOH, 9:1). 1H NMR (CF3COOD) d: 2.3 (s, 3H, Me), 11.1 (br. s, NH). IR (n/cm–1): 1595 (furoxan ring), 1695 (C=O), 3233 (NH). MS, m/z: 312 (M+). 3,3'-Azo-4,4'-bis(methylamino)furoxan 1c: yield 75%, mp 201–203 °C, Rf 0.32 (benzene:EtOAc, 9:1). 1H NMR ([2H6]acetone) d: 3.0 (d, Me).IR (n/cm–1): 1516, 1604 (furoxan ring), 2865, 2940 (CH), 3433 (NH). MS, m/z: 256 (M+). 3,3'-Azo-4,4'-bis(N-methylacetamido)furoxan 1d: yield 91%, mp 125– 126.5 °C, Rf 0.20 (benzene:EtOAc, 3:1). 1H NMR ([2H6]DMSO) d: 2.12 (s, MeCO), 3.40 (s, NMe). 13C NMR ([2H6]DMSO) d: 21.35 (MeCO, 1J 146.3 Hz), 35.34 (NMe, 1J 145.5 Hz), 126.66 (C-3 in furoxan ring), 149.68 (C-4 in furoxan ring), 170.28 (C=O). 4-Acetamido-3-(5-acetamido-4-nitro-1,2,3-triazol-2-yl)furoxan 2a. A suspension of 1b (1.0 g, 3.2 mmol) in AcOH (40 ml) and Ac2O (5 ml) was heated at 48–50 °C for 3 h. The reaction mixture was evaporated to 5 ml and cooled, and the precipitate was filtered off. Yield 65%, mp 141–143 °C, Rf 0.21 (CHCl3:PriOH, 9:1). 1H NMR (CF3COOD) d: 2.21 (s), 2.36 (s, 6H, 2MeCO), 11.43 (br. s, 2H, 2NH). 13C NMR (CF3COOD) d: 29.19 and 29.94 (2Me), 117.68 (C-3 in furoxan ring), 144.74 (C-4 in triazole ring), 146.02 (C-5 in triazole ring), 150.14 (C-4 in furoxan ring), 178.04, 178.81 (C=O). 14N NMR (CH3COOD) d: –26.6 (NO2). IR (n/cm–1): 1333, 1580 (NO2), 1640 (furoxan ring), 1708 (C=O), 2995, 3050 (CH), 3235 (NH). 4-Nitro-3-(4,5-dinitro-1,2,3-triazol-2-yl)furoxan 2b: yield 22%, mp 94.5– 95 °C (CHCl3, decomp.), Rf 0.51 (benzene). 13C NMR (CDCl3) d: 113.6 (C-3 in furoxan ring), 146.3 (C-4 and C-5 in triazole ring), 154.8 (C-4 in furoxan ring). 14N NMR (CDCl3) d: –37.0 (2NO2 of triazole ring), –39.0 (NO2 of furoxan ring). 15N NMR (CDCl3) d: 6.75 (N-2 in furoxan ring), 21.11 (N-5 in furoxan ring), 36.41 (N-1 and N-3 in triazole ring), 38.77 (NO2 of triazole ring), 40.05 (NO2 of furoxan ring), 162.75 (N-2 in triazole ring).IR (n/cm–1): 1320, 1332, 1570 (NO2), 1685 (furoxan ring). MS, m/z: 288 (M+). 3-Nitro-4-(4,5-dinitro-1,2,3-triazol-2-yl)furoxan 2c: yield 3%, oil. 13C NMR (CDCl3) d: 124.48 (C-3 in furoxan ring, 1J13C–14N 21.3 Hz), 145.41 (C-4 in furoxan ring), 147.96 (C-4 and C-5 in triazole ring). 14N NMR (CDCl3) d: –37 (Dn1/2 16 Hz, NO2 of triazole ring), –43 (Dn1/2 3.0 Hz, NO2 of furoxan ring). MS, m/z: 288 (M+). The mixture of 4(3)-(N-methylacetamido)-3(4)-(4-nitro-5-N-methylacetamido- 1,2,3-triazol-2-yl)furoxans 2d and 2e (2:1): total yield 38%, oil. 2d: 1H NMR ([2H6]acetone) d: 2.26 (s, 3H, MeCO of triazole ring), 2.30 (s, 3H, MeCO of furoxan ring), 3.48 (s, 3H, NMe of triazole ring), 3.55 (s, 3H, NMe of furoxan ring). 13C NMR ([2H6]acetone) d: 21.23 (MeCO of furoxan ring, 1J 141.6 Hz), 21.90 (MeCO of triazole ring), 31.10 (NMe of furoxan ring), 35.44 (NMe of triazole ring, 1J 142.3 Hz), 115.15 (C-3 in furoxan ring), 145.2 (C–NAc of triazole ring), 148.34 (C–NO2 in triazole ring), 150.42 (C-4 in furoxan ring), 171.16 (CO in triazole ring), 172.73 (CO in furoxan ring). 14N NMR ([2H6]acetone) d: –28.0 (NO2, Dn1/2 77 Hz). 2e: 1H NMR ([2H6]acetone) d: 2.05 (s, 3H, MeCO of furoxan ring), 2.20 (s, 3H, MeCO of triazole ring), 3.20 (s, 3H, NMe of furoxan ring), 3.35 (s, 3H, NMe of triazole ring). 13C NMR ([2H6]acetone) d: 21.53 (MeCO of furoxan ring, 1J 129.3 Hz), 22.03 (MeCO of triazole ring, 1J 142.3 Hz), 30.34 (NMe of furoxan ring, 1J 137.2 Hz), 35.34 (NMe of triazole ring, 1J 143.3 Hz), 115.94 (C-3 in furoxan ring, 3J 3.0 Hz), 145.2 (C–NAc in triazole ring), 148.56 (C–NO2 in triazole ring), 150.07 (C-4 in furoxan ring), 170.26 (CO in furoxan ring), 171.16 (CO in triazole ring).N O N Ph N N O N Ph N O O N O N Ph N N O N Ph N O i i O N O N Ph N N O N Ph N O O 1e 1f 1g Scheme 4 Reagents and conditions: i, AcOH, 110 °C, 10 h.N O N NO2 N N N O N NO2 O O N O N NHMe N N N O N NHMe O O i N N N O2N AcN N O N AcN O N N N O2N AcN N O N AcN 1h 1c 2d N O N N N N O N NAc O O 1d AcN Me Me iii Me Me ii 1:2 2e Me Me O Scheme 5 Reagents and conditions: i, CHCl3:Et2O = 3:1, MeNH2 (in gas phase), 20 °C, 40 min; ii, Ac2O (2 mol), H2SO4 (cat. amount), 20 °C, 30 min; iii, AcOH (or EtOAc, dioxane), 80–100 °C, 1.5–2 h.Mendeleev Communications Electronic Version, Issue 1, 1999 (pp. 1–44) The scheme suggested is consistent with the known methods of synthesis and the reactivity of 1,2,4-oxadiazoles, for example, the preparation of 1,2,4-oxadiazoles by thermal cyclization of a benzamidine derivative.10 Moreover, the thermal cleavage of the O(1)–N(2) bond under the action of nucleophiles to form a new heterocycle, in particular, 1,2,3-triazole,11–13 is the typical reaction of 1,2,4-oxadiazoles, including intramolecular reactions.In addition, it is noteworthy that both rearrangements in Scheme 6 agree with the general scheme (Scheme 3) of mononuclear heterocyclic rearrangements. This work was supported by the NATO Linkage grant nos. DISRM LG961369 and CNS 970584.References 1 A. N. Blinnikov, N. N. Makhova and L. I. Khmel’nitskii, Mendeleev Commun., 1999, 15. 2 R. Calvino, R. Fruttero, A. Gasco, V. Mortarini and S. Aime, J. Heterocycl. Chem., 1982, 19, 427. 3 L. Stefaniak, J. D. Roberts, M. Witanowski and G. A. Webb, Org. Magn. Reson., 1984, 22, 215. 4 L. I. Khmel’nitskii, S. S. Novikov and T. I. Godovikova, Khimiya furoksanov: reaktsii i primenenie (Chemistry of Furoxans: Reactions and Application), 2nd edn., Nauka, Moscow, 1996, p. 13 (in Russian). 5 B. Gohrmann and H. J. Niclas, J. Prakt. Chem., 1990, 332, 1054. 6 T. I. Godovikova, S. P. Golova, S. A. Vozchikova, E. L. Ignat’eva, M. V. Povorin, V. S. Kuz’min and L. I. Khmel’nitskii, Mendeleev Commun., 1995, 194. 7 A. J. Boulton, P. B. Ghosh and A. R. Katritzky, J. Chem. Soc. (B), 1966, 1004. 8 A. J. Boulton, A. R. Katritzky and A. M. Hamid, J. Chem. Soc. (C), 1967, 2005. 9 I. V. Ovchinnikov, N. N. Makhova, V. S. Kuz’min, A. N. Akimova and V. I. Pepekin, Dokl. Akad. Nauk SSSR, 1988, 359, 499 [Dokl. Chem. (Engl. Transl.), 1988, 359, 67]. 10 T. Fuchigami and K. Odo, Chem. Lett., 1974, 1139. 11 M. Ruccia, N. Vivona and G. Cusmano, J. Heterocycl. Chem., 1971, 8, 137. 12 P. Gramantieri, Gazz. Chim. Ital., 1935, 65, 102. 13 V. G. Yashunsky and L. E. Kholodov, Usp. Khim., 1980, 49, 54 (Russ. Chem. Rev., 1980, 49, 28). N O N N N N O N N O O 1 N R R N N N O2N AcN N O N AcN O Me O Me N N O N N O R O Me N NO2 N N R O Me 6 O R R 2a R = H 2d + 2e R = Me Scheme 6 Received: Moscow, 11th June 1998 Cambridge, 17th July 1998; Com. 8/04741C